tbuckley/cabot-search huggingface dataset:
CSIG-20. SYSTEMATIC REVIEW OF MOLECULAR TARGETED THERAPIES FOR ADULT-TYPE DIFFUSE GLIOMA: AN ANALYSIS OF CLINICAL AND LABORATORY STUDIES
Authors: Logan Muzyka, Nicolas Goff, Nikita Choudhary, Michael Koltz
Journal: Neuro-Oncology (2023)

Abstract Gliomas are becoming a frequent topic of investigation for molecular-targeted therapies. However, the current state of research in this area, particularly following the 2021 WHO guideline change, remains undefined. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to inform scientific progress. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, tumor type, molecular target, molecular pathway, and details pertaining to the molecular targeted therapy– namely the modality, dose, duration of treatment. 350 studies met inclusion criteria: 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. 119 ongoing clinical trials are also underway, per a detailed query of clinicaltrials.gov. GBM was the predominant tumor studied, with few studies mentioning IDH-mutant astrocytoma or oligodendroglioma. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, then immunotherapy and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were protein kinase pathways, followed by cell cycle/apoptosis, microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising as a novel target. This systematic review examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discusses its implications for clinical practice and future research. Published research encompasses clinical studies, laboratory testing of existing therapies, and identification of novel targets, with GBM as the focal point. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets were protein kinase pathways, with some variation in the prevalence of other pathways depending on study type.
TMET-13. DNA DAMAGE SIGNALING ACTIVATES GTP SYNTHESIS TO PROMOTE GLIOBLASTOMA TREATMENT RESISTANCE
Authors: Andrew J Scott, Alexandra O'Brien, Weihua Zhou, Jie Xu, Sravya Palavalasa, Ayesha Kothari, Kari Wilder-Romans, Angelica Lin, Zitong Zhao, Annabel Yang, Navyateja Korimerla, Erik Peterson, John Yang, Li Zhang, Anthony Andren, Sriram Chandrasekaran, Sriram Venneti, Jason Heth, Yoshie Umemura, Nathan Qi, John Woulfe, Meredith Morgan, Theodore Lawrence, Wajd Al-Holou, Costas Lyssiotis, Daniel Wahl
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common type of invasive brain tumor in adults and is uniformly fatal due to inherent resistance to radiation therapy (RT) and chemotherapy. Our group and others have found that metabolites can regulate DNA repair and therapy resistance in brain tumors, but little is known about how DNA damage regulates metabolic pathway activity in cancer. Here we show that following treatment with RT, GBMs increase rates of de novo guanylate synthesis in vitro and in orthotopic patient-derived xenograft models via signaling through the DNA repair protein DNA-PK. To determine if disrupting this regulation can augment GBM treatment efficacy, we combined an FDA-approved inhibitor of purine synthesis (mycophenolate mofetil, MMF) with chemoradiation in a variety of mouse models of GBM. Critically, targeting GTP synthesis improved the efficacy of both RT alone and chemoradiation in multiple patient-derived and syngeneic intracranial models. Our translational studies have shown that mycophenolic acid, the active metabolite of MMF, penetrates the blood-brain barrier at concentrations sufficient to inhibit GTP synthesis in GBMs of human patients. The phase 1 arms of our study, which are ongoing, are testing the safety and efficacy of combining MMF with standard of care chemoradiation for patients with primary and recurrent GBM.
TMET-17. LEVERAGING METABOLIC VULNERABILITIES INDUCED BY TERT EXPRESSION FOR GLIOBLASTOMA THERAPY <i>IN VIVO</i>
Authors: Suresh Udutha, Celine Taglang, Georgios Batsios, Anne Marie Gillespie, Pavithra Viswanath
Journal: Neuro-Oncology (2023)

Abstract Telomerase reverse transcriptase (TERT) is essential for telomere maintenance and tumor immortality. Although TERT is an attractive therapeutic target, targeting TERT directly is hampered by toxicity to stem cells that also rely on TERT for proliferation and the lag period before telomere attrition is observed. Targeting metabolic reprogramming associated with TERT is an alternate strategy. Our studies indicate that TERT is essential for redox homeostasis in glioblastoma cells (GBM; GBM6 and U251). Specifically, TERT increases levels of glutathione (GSH) via upregulation of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme in de novo GSH synthesis. Inhibiting GCLC using buthionine sulfoximine (BSO) or siRNA reduces synthesis of 13C-GSH from [U-13C]-glutamine and inhibits viability of GBM6 and U251 cells. However, GCLC inhibition causes a compensatory increase in synthesis of glutamate, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine via upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), the enzyme that generates glutamate from glutamine, and carbamoyl phosphate synthetase II (CPSII), the enzyme that converts glutamine to carbamoyl phosphate during pyrimidine biosynthesis. We then examined the therapeutic potential of inhibiting GLS and CPSII in combination with GCLC in GBMs. 6-diazo-5-oxy-L-norleucin (DON), a potent inhibitor of glutamine-utilizing enzymes including GLS and CPSII, synergizes with BSO in inhibiting viability of GBM6 and U251 cells. This effect is specific to TERT-expressing GBM cells because the combination of DON and BSO does not affect viability of normal astrocytes or astrocytomas that use the ALT pathway for telomere maintenance. Importantly, in vivo stable isotope tracing confirmed that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine and induces apoptotic death in mice bearing intracranial GBM6 tumors.Collectively, our studies highlight the therapeutic potential of targeting metabolic vulnerabilities induced by TERT expression in GBMs in vivo.
TMIC-04. IMMUNE PROFILING OF PEDIATRIC ONCOHISTONE GLIOMAS REVEALS DIVERSE MYELOID POPULATIONS AND TUMOR-PROMOTING BEHAVIORS
Authors: Augusto Faria Andrade, Danai Topouza, Michael McNicholas, Eduardo G Gonzalez Santiago, Antonella De Cola, Arne Gehlhaar, Selin Jessa, Bhavyaa Chandarana, Caterina Russo, Damien Faury, Geoffroy Danieau, Michele Zeinieh, Brian Krug, Yuhong Wei, Qing Wu, Emily M Nakada, Nikoleta Juretic, Valerie Larouche, Alexander G Weil, Roy Dudley, Jason Karamchandani, Sameer Agnihotri, Benjamin Ellezam, Daniela Quail, Yelizaveta Konnikova, Claudia Kleinman, Logan Walsh, Manav Pathania, Nada Jabado
Journal: Neuro-Oncology (2023)

Abstract Pediatric high-grade gliomas pHGG are lethal and frequently bear missense mutations in histone H3, which drive tumorigenesis by altering the epigenome and cell fate/differentiation. While previous studies showed intrinsic contingencies associated with tumor development, limited information exists on the tumor microenvironment (TME) and immune cells for these tumors. To define the immune landscape of pediatric tumors at single-cell resolution, we profiled and compared 69 pediatric gliomas samples using the Chromium 10X technologies, H3.3 K27M (N=19) and G34R (N=16) mutant tumors, low-grade gliomas (N=11) and ependymomas (N=23). Additionally, to enable the spatial resolution of immune lineages, we performed Imaging Mass Cytometry (IMC) on H3-mutant samples (H3.3 K27M (N=7) and G34R (N=5)). We demonstrate that pediatric histone H3-mutant gliomas are highly infiltrated by myeloid cells, more specifically resident microglia, bone-marrow derived macrophages (BMDM) and monocytes, and are devoid of lymphoid infiltration. Different myeloid subsets were found to interact with H3-mutant cancer cells. Classical BMDM showed strong interactions with H3-mutant cancer cells while monocytes subsets showed tendency to interact only with G34R cells. We have generated a novel H3.3K27M glioma immunocompetent murine model, establishing a highly-penetrant and reliable tool. H3.3K27M murine tumors recapitulated the TME from human tumors, showing great myeloid infiltration. Using in vivo orthotopic serial engraftments, we observed that secondaries transplanted tumors had a significantly worse survival, possessing a less diverse immune infiltration compared to initial engraftments and a dominant presence of myeloid cells. Interestingly, in vivo myeloid depletion combined with PD-1 blockade extended overall mice survival. Our findings provide a valuable characterization of the biology of these tumors, reinforcing the several roles of myeloid cells in the context of pediatric brain tumours, providing a framework for understanding the H3.3K27M and G34R tumors, including other pediatric gliomas, and designing future immunotherapies.
RADT-29. TARGETING ANDROGEN RECEPTOR FOR GLIOBLASTOMA: A NOVEL RADIOSENSITIZING THERAPY THROUGH TGF-Β/LIF/STAT3 PATHWAY AND IMMUNOMODULATION
Authors: Rubayat Khan, Nan Zhao, Chi Zhang
Journal: Neuro-Oncology (2023)

Abstract In the search for more effective treatments for glioblastoma (GBM), a primary brain malignancy, we explored the synergistic effects of androgen receptor antagonists (ARAs) and radiotherapy (RT). Prior research indicated that ARA treatment alone improved survival in GBM mouse models, primarily through the suppression of glioma cancer stem cells. Our recent investigations aimed to ascertain the radiosensitizing effects of ARAs when combined with RT. Initial in vitro experiments, using proliferation assays on cultured GBM cells, showed only mild radiosensitizing effects. ARAs, however, induced apoptosis, enriched the G2/M phase in cell cycling, and decreased expression in numerous DNA repair genes, which were confirmed through RNA sequencing and TCGA database analyses. Additionally, Western blotting revealed that ARAs modulated SMAD2/3 phosphorylations differentially in c-terminal and linker domains in the TGF-β pathway and suppressed LIF-STAT3 signaling. This intricate mechanism involving the alteration of key cellular signaling pathways led us to hypothesize that ARAs may potentiate RT in vivo. To validate this hypothesis, we conducted in vivo studies using an orthotopic GBM mouse model. Substantial synergy was observed between ARAs and brain RT, with combined ARA and RT treatment achieving 100% long-term survival and establishing immune memory, a significant increase compared to &amp;lt;50% survival for the ARA only group and 0% for the RT only group. Notably, we identified significant immunostimulating effects within the tumor microenvironment and systemically, as determined by immunohistochemistry and flow cytometry on peripheral blood and spleen, respectively. Our findings demonstrate that although ARAs show mild radiosensitizing effects on GBM cells in vitro, they significantly synergize with RT in vivo, via alterations in TGF-β/LIF/STAT3 signaling pathways which have been known to influence immunomodulation. The local and systemic immunomodulatory effects demonstrated in our studies by ARA treatment warrant further study combining ARA with immunotherapeutics.
PATH-61. NGS DATA INFLUENCE ON CLINICIAN DECISION-MAKING ACROSS PRIMARY BRAIN TUMORS AT NORTHWESTERN UNIVERSITY
Authors: Adam Eckburg, Jordan John, Priya Kumthekar
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Next-generation sequencing (NGS) is routinely completed for systemic solid tumors; however, its utility is unclear in brain tumors. Our study sought to investigate and compare the impact of NGS on treatment decision-making for glioblastoma and other primary brain tumors. METHODS An IRB-approved retrospective chart review was conducted with patients at Northwestern University who were diagnosed with a primary brain tumor receiving NGS sequencing between October 2013 and February 2020. Tempus reports for each in-house sequencing event along with pertinent medical information from the electronic medical record (EMR) was extracted. Primary brain tumor types assessed included glioblastoma, astrocytoma, oligodendroglioma, and other rare subtypes (including meningioma, ependymoma, ganglioma, pleomorphic xanthoastrocytoma, atypical teratoid rhabdoid tumors, glioneuronal tumors, and CNS lymphomas). NGS-impacted decision-making was defined as a physician prescribing a targeted treatment that corresponded with an actionable mutation in the Tempus report. RESULTS NGS was completed in 261 patients with glioblastoma and 121 patients with other primary brain tumors. NGS impacted decision-making in 12.6% (33) of glioblastoma patients and 9.1% (11) of other brain tumor patients. These figures in grades 1-3 astrocytoma and oligodendroglioma were 9.1% (4 of 44) and 8.1% (3 of 37), respectively. NGS impacted treatment in 10.0% (4 of 40) of all remaining subtypes analyzed. Overall, NGS sequencing data influenced clinical decision-making 11.5% of the time across all brain tumor types. Across the 382 patients assessed, EGFR copy number gain or GOF mutations were targeted most often (52.3% of all mutations targeted), followed by BRAF (11.4%) and IDH1 (11.4%). CONCLUSIONS NGS influences treatment decisions less often in primary brain tumors compared to other systemic cancers; however, NGS should still be considered in primary brain tumor patients, as it impacts treatment decision-making across subtypes. As more targeted therapies become available for CNS tumors, the utility of NGS will only increase.
CTIM-30. A PHASE 1B, OPEN-LABEL, DOSE-ESCALATION TRIAL OF THE DELTA-LIKE LIGAND 3 (DLL3)/CD3 IGG-LIKE T CELL ENGAGER, BI 764532, IN PATIENTS WITH DLL3-POSITIVE GLIOMA
Authors: Martin van den Bent, Patrick Roth, Ghazaleh Tabatabai, Michael C Burger, Maria Martinez-Garcia, Louisa von Baumgarten, Richard Greil, Matus Studeny, Monika Simetzberger, Meiruo Liu
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with progressive diffuse gliomas have limited treatment options. DLL3, a Notch ligand, is expressed on most diffuse gliomas. BI 764532, a humanized IgG-like T cell engager, binds selectively to DLL3-positive cells and promotes T cell-mediated cytotoxicity. Preclinical data showed activity of BI 764532 against intracranial tumors. In an ongoing first-in-human trial in patients with DLL3-positive small-cell lung carcinoma and other neuroendocrine carcinomas (NECs) including extrapulmonary NECs and large-cell NECs of the lung (NCT04429087), BI 764532 exhibited promising efficacy and manageable tolerability. Here we describe a planned Phase Ib dose-escalation/expansion trial of BI 764532 monotherapy in patients with DLL3-positive refractory/relapsed diffuse glioma. METHODS The dose-escalation part will include ~12–20 patients (≥3 patients per dose level) from 12 sites across Europe/USA. Dose escalation will be guided by Bayesian logistic regression model with overdose control. BI 764532 will be administered intravenously. Treatment will continue until disease progression, undue toxicity, informed consent withdrawn, or other reasons requiring treatment discontinuation. Once a recommended dose for expansion is established, ~15 patients from Europe will be treated in a dose-expansion phase. Key inclusion criteria: ≥18 years old; histologically confirmed primary progressive diffuse glioma who have failed on standard-of-care therapies; DLL3-positivity by IHC on archived tumor tissue by central pathology review. Key exclusion criteria: extracranial metastatic or leptomeningeal disease; previous treatment with DLL3-targeting therapies; prior treatment with bevacizumab/other anti-VEGF/anti-angiogenic treatment ≤6 months prior to first administration of BI 764532; persistent toxicity from previous treatments that has not resolved to ≤CTCAE Grade 1; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (escalation phase); DLTs during the entire treatment period (expansion phase). Other objectives include pharmacokinetics, pharmacodynamics, preliminary efficacy and evaluation of DLL3 as a potential biomarker.
TMIC-02. SEX DIFFERENCES IN IMMUNE RESPONSE IN A MURINE GLIOBLASTOMA RESECTION MODEL CONFER A FEMALE SURVIVAL ADVANTAGE
Authors: Josephine Volovetz, Juyeun Lee, Justin Lathia
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of 15-20 months, despite standard of care treatment, which includes surgical resection, radiation, and chemotherapy. GBM is 1.6 times more common in males and overall survival can be up to 10 months shorter in males. Females are more responsive to standard of care therapy, but the mechanism behind these differences is not clear. The immune system is known to be suppressed in GBM patients, and recent studies have found sex differences in immune response. While pre-clinical GBM models are used to interrogate pathophysiology and response to therapeutic interventions, few of these models include surgical resection, despite its role in the standard of care for patients and as a defining therapy in prolonging survival. We developed a pre-clinical GBM resection model to evaluate whether there is a sex bias in survival and to interrogate sex-specific immune changes after surgery. We found that C57BL/6 mice implanted with syngeneic GBM cells demonstrate a sex bias after surgical resection, with males surviving for a median of 24 days compared to 33 days for females. To understand how the immune response is affected by surgical resection in males and females with GBM, we performed flow cytometry to characterize the immune phenotype and found that female mice who underwent resection of their tumors had significantly higher levels of CD4+ T cells in their resection cavity than male mice who underwent resection. The immune phenotype will be further characterized over time to evaluate how it evolves in each sex. These data support prior observations that the mechanisms of immunosuppression are different in males and females. They further underscore the complexity of sex bias in GBM and the need to account for surgical resection and sex in pre-clinical models to investigate next-generation therapeutic strategies.
TMIC-17. THE ROLE OF ICAM1 IN GLIOBLASTOMA TUMORIGENESIS UNDER HYPOXIC CONDITIONS
Authors: Sheila Mansouri, Kaviya Devaraja, Gelareh Zadeh, Olivia Singh, Hafsah Ali, Qinxqia Wei, Julio Sosa, Vikas Patil
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a deadly brain cancer in adults with limited treatment options. Cell adhesion molecules (CAMs) mediate cell-cell interactions and migration. Intercellular adhesion molecule 1 (ICAM-1) is a CAM expressed by various cell types in solid tumors, including macrophages, tumor and endothelial cells. We previously demonstrated that ICAM-1 expression is linked to shorter overall survival in GBM patients. We observed elevated ICAM-1 levels in hypoxic regions of GBMs. Considering the role of tumor-associated macrophages (TAMs) in GBM tumorigenicity, our objective was to investigate how ICAM-1 expression in TAMs contributes to GBM growth within the hypoxic tumor microenvironment (TME). We employed a comprehensive approach utilizing in vitro and in vivo models, as well as genomic analyses at both bulk and single-cell levels, to elucidate the association between ICAM-1 and TAMs in tumorigenicity. Our findings demonstrated that injecting GBM cells into ICAM-1 knockout mice led to prolonged survival, smaller tumors, reduced macrophage infiltration, and enhanced M1-like polarization of TAMs. Additionally, bone marrow reconstitution experiments confirmed the tumor-promoting role of ICAM-1-expressing TAMs. Cell deconvolution, immunohistochemical, and flow cytometry analyses of mouse tumors supported these findings. Gene set enrichment analysis of differentially expressed genes in xenografted tumors revealed that ICAM-1 presence upregulated key tumorigenic pathways, including epithelial-mesenchymal transition, IL2-STAT5, TNF-α via NFκB, IL6-JAK-STAT3, and RAS/MAPK. In vitro analysis indicated that ICAM-1 promoted macrophage migration and polarization towards M2-like state, which was further augmented by hypoxia-induced ICAM1 expression. Flow cytometry, cytometry by time of flight (cyToF), and single-cell RNA sequencing analysis of human and mouse GBMs revealed elevated ICAM-1 expression in hypoxic TAMs, suggesting the hypoxic microenvironment promotes the tumorigenic functions of TAMs. In conclusion, ICAM1 likely enhances GBM tumorigenesis by promoting TAM migration into the TME. Furthermore, environmental factors such as hypoxia contribute to increased ICAM-1 expression in TAMs, further exacerbating GBM tumorigenicity.
MODL-39. ELUCIDATING THE TRANSCRIPTOMIC LANDSCAPE OF METASTATIC PEDIATRIC MEDULLOBLASTOMA
Authors: Ana Isabel Castillo Orozco, Masoumeh Aghababazadeh, Marjan Khatami, Geoffroy Danieau, Wajih Jawhar, Niusha Khazaei, Livia Garzia
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB) is a highly aggressive and the most common brain tumor in childhood. MB presents a high intertumoral heterogeneity, with at least four molecular subgroups (SHH, WNT, Group 3, and Group 4) identified. MB can metastasize to the leptomeningeal space, known as Leptomeningeal Disease (LMD) and its presence is a universal predictor of poor outcome among MB patients. Metastatic MB is predominantly found in the MB Group 3 type. Although LMD represents a main clinical challenge, its molecular mechanisms remain poorly characterized. Recent research has shown that primary and MB metastasis diverge dramatically. Our work has focused on establishing therapy naïve Group 3 Patient-Derived Xenografts that faithfully replicate the nature of primary and metastatic Medulloblastoma with the aim to perform comparative genomic and transcriptomic analyses between these models to identify genetic drivers/pathways that sustain metastatic MB or leptomeningeal disease. Our results show various signaling pathways enriched across LMD models, such as protein secretion and oxidative phosphorylation. We also have identified differentially expressed genes, where sets of genes have shown to be present in more than one PDX model, such as members of the Solute Carriers family (SLC44A3 and SLC17A9) and FCGBP. Retrieval of short variants from RNAseq data has not revealed thus far mutations enriched in LMD, suggesting these changes could be attributed to epigenetic disruption rather than genetic changes. In conclusion, our results support the notion that primary and LMD are transcriptionally different, with various enriched pathways and sets of DEG among LMD Group 3 PDX models. These findings are in progress for functional validation. Work is currently being done to profile the epigenome of LMD by correlating transcriptomic data with active chromatin markers such as H3K27ac and H3K4me1. Through these approaches, we aim to elucidate the genetic dependencies of metastatic Medulloblastoma that will help for targeted therapies.